The mammalian ovary has two main functions—producing mature oocytes for fertilization and secreting hormones for maintaining the ovarian endocrine functions. Both functions are vital for female reproduction. Primordial follicles are composed of flattened pre-granulosa cells and a primary oocyte, and activation of primordial follicles is the first step in follicular development and is the key factor in determining the reproductive capacity of females. The recent identification of the phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway as the key controller for follicular activation has made the study of primordial follicle activation a hot research topic in the field of reproduction. This review systematically summarizes the roles of the PI3K/PTEN signaling pathway in primordial follicle activation and discusses how the pathway interacts with various other molecular networks to control follicular activation. Studies on the activation of primordial follicles have led to the development of methods for the in vitro activation of primordial follicles as a treatment for infertility in women with premature ovarian insufficiency or poor ovarian response, and these are also discussed along with some practical applications of our current knowledge of follicular activation.

Currently, no effective treatment exists for infertility associated with premature ovarian insufficiency (POI) because affected patients lack hormone-responsive antral follicles. By screening a Food and Drug Administration (FDA)–approved drug library, we identified finerenone, a kidney disease medication, as a promising drug for restoring fertility in POI. Finerenone stimulated follicle development in aged mice and restored antral follicle development in patients with POI following oral administration, resulting in mature oocytes and embryos. Mechanistically, finerenone reduced fibrotic deposition in the ovarian stroma, alleviating collagen-mediated suppression of follicular development. Building on this insight, we identified additional FDA-approved oral antifibrotic drugs as potential treatments for POI-related infertility. Our findings highlight the ovarian stroma—rather than the follicles themselves—as the key therapeutic target and offer potential therapeutic leads for POI-related infertility.

In mouse early pachytene spermatocytes, the X and Y chromosomes undergo rapid non-homologous (NH) synapsis and desynapsis, but the functional significance remains unknown. Here, we report that pachynema-specific knockout of Speedy A (SpdyA) from telomeres caused persistent Y-X NH synapsis , with the entire Y axis synapsed onto the X axis. This persistent Y-X NH synapsis did not interrupt meiotic sex chromosome inactivation, recombination, or sex body formation, but it disrupted X-Y loop-axis organization and homologous X-Y desynapsis, leading to spermatocyte death. Similarly, persistent Y-X NH synapsis was also observed in pachytene spermatocytes lacking TRF1, where SpdyA was frequently lost from the X-Y non-pseudoautosomal region (non-PAR) telomeres. Mechanistic studies revealed that Serine 48 of SUN1 is a key SpdyA/CDK2 phosphorylation site required for Y-X NH desynapsis. We propose that SpdyA governs Y-X NH desynapsis by stabilizing the linkage between the X-Y non-PAR telomeres and their LINC complexes, and that this process is regulated independently from other aspects of pachynema progression. Our findings suggest a key role for Y-X NH desynapsis in establishing proper X-Y loop-axis organization.

The lack of hormone-responsive follicles is a major challenge in treating infertility/subfertility in women with premature ovarian insufficiency or diminished ovarian reserve. In this study, we demonstrate that securinine, a neurological drug, can be repurposed to promote small follicle growth. In aged mice, intraovarian injection of securinine significantly enhances follicular development and improves fertility, yielding healthy offspring. Mechanistically, single-cell RNA sequencing reveals that securinine promotes follicular development by alleviating the negative regulation from the stromal extracellular matrix on granulosa cells. Furthermore, intraovarian injection of securinine in aged cynomolgus macaques effectively stimulates the development of small follicles into large antral follicles. Our findings highlight securinine as a promising candidate for ultrasound-guided ovarian injection for treating infertility/subfertility in women with premature ovarian insufficiency, diminished ovarian reserve, or advanced maternal age. As a small molecule drug, intraovarian securinine injection offers clinical advantages that avoid complex preparation procedures required for platelet-rich plasma or stem cell-based therapies.